Turnover of type I and III collagen predicts progression of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of fibrillar collagens in the alveolar space resulting in reduced pulmonary function and a high mortality rate. Biomarkers measuring the turnover of type I and III collagen could provide valuable information for prognosis and treatment decisions in IPF. METHODS: Serological biomarkers reflecting the formation of type III collagen (PRO-C3) and degradation of type I (C1M) and III collagen (C3M) were evaluated in a real-world cohort of 178 newly diagnosed IPF patients. Blood samples and clinical data were collected at baseline, six, and 12 months. Baseline and longitudinal biomarker levels were related to disease progression of IPF (defined as ≥ 5% decline in forced vital capacity (FVC) and/or ≥ 10% decline in diffusing capacity for carbon monoxide (DLco) and/or all-cause mortality at 12 months). Furthermore, we analysed differences in percentage change of biomarker levels from baseline between patients receiving antifibrotic treatment or not. RESULTS: Increased baseline levels of type I and III collagen turnover biomarkers were associated with a greater risk of disease progression within 12 months compared to patients with a low baseline type I and III collagen turnover. Patients with progressive disease had higher serum levels of C1M (P = 0.038) and PRO-C3 (P = 0.0022) compared to those with stable disease over one year. There were no differences in biomarker levels between patients receiving pirfenidone, nintedanib, or no antifibrotics. CONCLUSION: Baseline levels of type I and III collagen turnover were associated with disease progression within 12 months in a real-world cohort of IPF patients. Longitudinal biomarker levels of type I and III collagen turnover were related to progressive disease. Moreover, antifibrotic therapy did not affect type I and III collagen turnover biomarkers in these patients. PRO-C3 and C1M may be potential biomarkers for a progressive disease behavior in IPF.

Identification of heterogenous treatment response trajectories to anti-IL6 receptor treatment in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with fluctuating course of progression. Despite substantial improvement in treatments in recent years, treatment response is still not guaranteed. The aim of this study was to identify variation in Disease Activity Score 28 (DAS28) of RA patients in response to Tocilizumab, and to investigate both molecular and clinical factors influencing response. Clinical and biochemical data for 485 RA patients receiving Tocilizumab in combination with methotrexate were extracted from the LITHE phase III clinical study (NCT00106535), and post-hoc analysis conducted. Latent class mixed models were used to identify statistically distinct trajectories of DAS28 after the initiation of treatment. Biomarker measurements were then analysed cross-sectionally and temporally, to characterise patients by serological biomarkers and clinical factors. We identified three distinct trajectories of drug response: class 1 (n = 85, 17.5%), class 2 (n = 338, 69.7%) and class 3 (n = 62, 12.8%). All groups started with high DAS28 on average (DAS28 > 5.1). Class 1 showed the least reduction in DAS28, with significantly more patients seeking escape therapy (p < 0.001). Class 3 showed significantly higher rates of improvement in DAS28, with 58.1% achieving ACR response levels compared to 2.4% in class 1 (p < 0.0001). Biomarkers of inflammation, MMP-3, CRP, C1M, showed greater reduction in class 3 compared to the other classes. Identification of more homogenous patient sub-populations of drug response may allow for more targeted therapeutic treatment regimens and a better understanding of disease aetiology.

Processed meat intake and incidence of colorectal cancer: a systematic review and meta-analysis of prospective observational studies.

The objective was to use accumulated evidence to explore the association between processed meat intake and risk of colorectal cancer (CRC) and to investigate the reliability of associations by evaluating patterns of risk by study population characteristics and research quality parameters. We included 29 observational prospective cohort studies with relative risk estimates and 95% confidence intervals for CRC according to various levels of processed meat consumption. Risk of bias was assessed using Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I) tool. Data sources were PubMed and Embase up to January 2017. The summary relative risks for high versus low processed meat consumption and risk of CRC, colon, and rectal cancer were 1.13 (95% CI: 1.01, 1.26), 1.19 (95% CI: 1.09, 1.31), and 1.21 (95% CI: 0.98, 1.49), respectively. Similar estimates were observed for the dose-response analyses. Heterogeneity across studies was detected in most analytical models. The overall judgment showed that two out of 29 studies had a moderate risk of bias, 25 had a serious risk of bias, and 2 had a critical risk of bias. The bias domains most often rated critical were bias due to risk of confounding, bias due to missing data, and selective outcome reporting bias. Although this meta-analysis indicates a modest association between processed meat intake and an increased risk of CRC, our assessment of internal validity warrants a cautious interpretation of these results, as most of the included studies were judged to have serious or critical risks of bias.

Habitual coffee consumption and changes in measures of adiposity: a comprehensive study of longitudinal associations.

BACKGROUND: A relationship between change in coffee consumption and reduced long-term weight gain has been suggested, but current evidence is inconsistent. OBJECTIVE: To examine longitudinal associations between coffee consumption and changes in body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI), body fat percentage (BF %) and waist circumference (WC). DESIGN: The study consisted of 2128 participants from the Danish part of the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) cohort with repeated information on coffee consumption, adiposity measures and covariates during an 11-year period. Linear regression analyses were conducted to assess the associations between baseline coffee consumption and subsequent change in adiposity measures. The same analyses were conducted analyzing associations between change in coffee consumption and concurrent as well as subsequent changes in adiposity measures. RESULTS: We found no consistent evidence of associations between baseline coffee consumption and subsequent 6-year changes in adiposity measures. A statistically significant association between increased coffee consumption over a 6-year period and decreased concurrent gain in BMI, FMI, BF % and WC (-0.05 kg m-2 (95% confidence interval (CI): -0.07, -0.02), -0.04 kg m-2 (95% CI: -0.06, -0.02), -0.08% (95% CI: -0.13, -0.04) and -0.23 cm (95% CI: -0.34, -0.12), respectively, per 1 cup day-1 increase in coffee consumption) was found. No association was seen between change in coffee consumption and concurrent change in FFMI. Moreover, an initial change in coffee consumption during the first 5-year period was not associated with change in adiposity during the subsequent 6-year period. CONCLUSIONS: Increased coffee consumption was associated with a decreased concurrent gain in body weight, fat mass and waist circumference, but the associations were weak. Moreover, a causal relationship could not be established, as we found no evidence of associations between an initial change in coffee consumption and subsequent change in adiposity.

Composition and effect of blending of noncoagulating, poorly coagulating, and well-coagulating bovine milk from individual Danish Holstein cows.

The aim of the present investigation was to study the underlying causes of noncoagulating (NC) milk. Based on an initial screening in a herd of 53 Danish Holstein-Friesians, 20 individual Holstein-Friesian cows were selected for good and poor chymosin-induced coagulation properties; that is, the 10 cows producing milk with the poorest and best coagulating properties, respectively. These 20 selected cows were followed and resampled on several occasions to evaluate possible changes in coagulation properties. In the follow-up study, we found that among the 10 cows with the poorest coagulating properties, 4 cows consistently produced poorly coagulating (PC) or NC milk, corresponding to a frequency of 7%. Noncoagulating milk was defined as milk that failed to form a coagulum, defined as increase in the storage modulus (G') in oscillatory rheometry, within 45min after addition of chymosin. Poorly coagulating milk was characterized by forming a weak coagulum of low G'. Milk proteomic profiling and contents of different casein variants, ionic contents of Ca, P and Mg, κ-casein (CN) genotypes, casein micelle size, and coagulation properties of the 4 NC or PC samples were compared with milk samples of 4 cows producing milk with good coagulation properties. The studies included determination of production of caseinomacropeptide to ascertain whether noncoagulation could be ascribed to the first or second phase of chymosin-induced coagulation. Caseinomacropeptide was formed in all 8 milk samples after addition of chymosin, indicating that the first step (cleavage of κ-CN) was not the cause of inability to coagulate. Furthermore, the effect of mixing noncoagulating and well-coagulating milk was studied. By gradually blending NC with well-coagulating milk, the coagulation properties of the well-coagulating samples were compromised in a manner similar to titration. Milk samples from cows that consistently produced NC milk were further studied at the udder quarter level. The coagulation properties of the quarter milk samples were not significantly different from those of the composite milk sample, showing that poor coagulation traits and noncoagulation traits of the composite milk were not caused by the milk quality of a single quarter. The milk samples exhibiting PC or NC properties were all of the κ-CN variant AA genotype, and contained casein micelles with a larger mean diameter and a lower fraction of κ-CN relative to total CN than milk with good coagulation properties. Interestingly, the relative proportions of different phosphorylation forms of α-CN differed between well-coagulating milk and PC or NC milk samples. The PC and NC milk samples contained a lower proportion of the 2 less-phosphorylated variants of α-CN (α(S1)-CN-8P and α(S2)-CN-11P) compared with samples of milk that coagulated well.

Effect of health-promoting posters placed on the platforms of two train stations in Copenhagen, Denmark, on the choice between taking the stairs or the escalators: a secondary publication.

OBJECTIVE: The purpose of this study was to determine whether posters placed on the platforms of two train stations in Copenhagen, promoting use of the stairs, would encourage people to use the stairs rather than the adjacent escalator. An additional purpose was to see if the effect of the intervention was maintained for a week after the poster was removed. MEASUREMENTS: The number of people using stairs and escalators at Copenhagen Central Station and Østerport Train Station in Copenhagen was recorded before and during posters promoting stair use were placed on the platforms, and a week after the posters were removed. Two years after the posters were removed, data were collected for 1 week at Østerport Train Station (long-term post-intervention). RESULTS: At Copenhagen Central Station, the overall stair use increased from 12% before the intervention to 16% (P<0.0001) during the intervention, giving an odds ratio (OR) of 1.5 for stair use. At Østerport Train Station in Copenhagen, the overall stair use increased from 23 to 31% during the intervention (P<0.0001), and dropped to 27% (P<0.0001) after the intervention (during the intervention, OR=1.5 (P<0.0001); after the intervention, OR=1.2 (P<0.0001)). At the long-term post-intervention recording, the overall stair use was 25%, which was not significantly different from the stair use found before the intervention. DISCUSSION: Posters promoting stair use placed on the platforms of train stations can result in increased stair use, during and after 1 week of intervention, and thereby seem useful only when up and immediately following intervention in changing health-promoting behavior among Danish men and women. These results agree well with results from other countries.

Imprecise methods may both obscure and aggravate a relation between fat and breast cancer.

Bias in diet reporting may be both random and non-random, and may be found with simpler as well as more advanced dietary instruments. A random bias will contribute to obscure relations between diet and disease. A systematic bias may obscure or aggravate such associations. Underreporting of non-protein energy has been found to be substantial, particularly among those who are obese or have high dietary intakes. Such a non-random bias on the group level would tend to aggravate associations between dietary non-protein and disease. Whether the net result of the random and non-random bias aggravates or obscures relations depends on the relative magnitude of the two.

Clinical manifestations of mannan-binding lectin deficiency.

Mannan-binding lectin (MBL) is a plasma protein of the innate immune system with the ability to initiate antimicrobial and inflammatory actions. MBL deficiency is common. More than 10% of the general population may, depending on definition, be classified as MBL deficient, underlining the redundancy of the immune system. Ongoing research attempt to illuminate at which conditions MBL deficiency may lead to disease. With examples, this review illustrates the diversity of results obtained so far.

M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement.

Ficolins play a role in the innate immune defence as pathogen-associated molecular pattern recognition molecules. Three ficolins are found in humans: H-ficolin, L-ficolin and M-ficolin. L-ficolin and H-ficolin circulate in blood in complexes with mannan-binding lectin-associated serine proteases (MASPs) and are capable of activating the complement system. L-ficolin shows affinity for acetylated compounds and binds to various capsulated strains of bacteria. H-ficolin has been shown to bind Aerococcus viridans. Less is known about M-ficolin, but it is thought to be present only on monocytes. We have synthesized recombinant M-ficolin and find that it, in a manner similar to L-ficolin, is able to bind to acetylated compounds and to associate with recombinant MASP-2. Upon binding to M-ficolin ligands, the associated MASP-2 zymogen is activated and cleaves C4, thus triggering the complement system. We developed a monoclonal rat anti-human-M/L-ficolin antibody and verified by flow cytometric analysis the presence of ficolin on the surface of peripheral blood monocytes.

Two-photon photosensitized production of singlet oxygen.

Singlet molecular oxygen (a(1)Delta(g)) has been produced and optically detected upon two-photon nonlinear excitation of a sensitizer with a focused laser beam. The experiments were performed using toluene solutions with either a substituted difuranonaphthalene or a substituted distyryl benzene as the sensitizer. The data indicate that the two-photon absorption cross sections of the difuranonaphthalenes are comparatively large and depend significantly on the functional groups attached to the chromophore. The time-resolved 1270 nm phosphorescence signals used to characterize the production of singlet oxygen are limited in much the same way as signals from other two-photon spectroscopic studies (e.g., weak signals that can be masked by scattered radiation). Nevertheless, the two-photon singlet oxygen signals also reflect the unique advantages of this nonlinear optical technique (e.g., depth penetration in the sample afforded by irradiation in a spectral region void of the more dominant one-photon linear transitions and spatial resolution afforded by irradiation with a focused laser beam).

Epidemiology of respiratory syncytial virus infection requiring hospitalization in East Denmark.

BACKGROUND: Prophylaxis against infection caused by respiratory syncytial virus (RSV) with high titered RSV immunoglobulin or humanized antibody may soon be available in Europe. OBJECTIVE: To study the epidemiology of RSV infections requiring hospitalization in infants <6 months in East Denmark to provide a rational basis for decisions concerning prophylaxis against RSV. METHOD: Populat ion-based retrospective review of case records of infants <6 months admitted to pediatric departments with RSV infection in East Denmark from November 1, 1995, to April 30, 1996. RESULTS: Data were obtained from 459 infants. Seventy-three had predisposing conditions: prematurity, 49; pulmonary disease, 2; congenital heart disease, 7; neurologic disease, 6; others, 9. One preterm infant had bronchopulmonary dysplasia. The incidence of RSV infection requiring hospitalization in East Denmark among infants <6 months was estimated to be 34/1000/season. It was 32/1000/season among term infants and 66/ 1000/season among preterm infants (P<0.001). Infants with predisposing conditions and/or nosocomial infection (n = 24) had significantly more severe courses than otherwise healthy infants (P<0.01). One-hundred thirty infants received respiratory support by nasal continuous positive airway pressure, but only six required mechanical ventilation. No infants died. CONCLUSION: The course of RSV disease in East Denmark was milder than reported elsewhere, possibly as a result of the low prevalence of bronchopulmonary dysplasia in Denmark. However, RSV constitutes a considerable burden to the Danish pediatric health care system, and therefore prophylaxis against RSV is desirable.

Arrhythmogenic right ventricular dysplasia as a cause of sudden death.

Arrhythmogenic right ventricular dysplasia (ARVD) is a poorly understood and often underdiagnosed disorder of the right ventricle, characterized by replacement of myocardium by fibroadipose tissue, arrhythmic manifestations, and sudden death. The disease occurs in families and is inherited as an autosomal dominant trait. This report describes five cases of ARVD identified by autopsy. In three of the cases, sudden death occurred in the young (16-28 years old) during or shortly after exercise. In another case, a 46-year-old man with no relevant medical history was found dead in his bathroom. In the last case, a 57-year-old woman died from pulmonary thromboembolism. In none of the subjects had the disease been diagnosed or suspected before death. Only one (a 21-year-old man) had previous typical symptoms of the disease. Autopsy examination showed right ventricle dilation and, in four cases, cardiomegaly. The right ventricular myocardium of all hearts was almost replaced by adipose tissue and to a variable degree by fibrous tissue, while the left ventricle myocardium demonstrated no, or only scattered, fibro-fatty infiltration. Postmortem diagnosis of ARVD can be important in identifying possible affected family members in order to initiate treatment.

The impact of 123I-meta-iodobenzylguanidine scintigraphy on diagnostics and follow-up of neuroblastoma.

The present retrospective study includes all children suspected for having neuroblastoma, admitted to Odense University Hospital in September 1984 through December 1993. Thirty-six children at the age range of 1 month to 14 years and 10 month were investigated with 123I-metaiodobenzylguanidine (MIBG). Nineteen children had histologically verified neuroblastoma. Several MIBG scintigraphic examinations were made in all but one of these 19 children. Positive MIBG scintigraphy strengthened the diagnosis and indicated the volume and location of the tumour at diagnosis and during the treatment period. In a few patients only there was some disagreement between results obtained with MIBG scintigraphy and standard investigations as CT-scanning or ultrasonography. MIBG scintigraphy in all cases turned out to be the most sensitive modality.

[99mTc anti-carcinoembryonic antigen in colorectal cancer]. / 99mTc-anti-karcinoembryonalt antigen ved kolorektal cancer.

This investigation is a part of a phase three multicentre immunoscintigraphy study of a technetium-99m labelled monoclonal antibody (Mab), BW 431/26, directed against carcino-embryonic antigen (CEA). Ten patients with recently colonoscopically verified primary colorectal cancer were evaluated. In nine of ten patients colorectal cancers were detected by wholebody immunoscintigraphy and by single photon emission computerized tomography (SPECT). The ten patients were operated upon, and in nine cases immunohistochemical investigations were performed. Immunohistochemical investigation of nine tumour specimens show that CEA was present in much higher concentrations in the tumour than in normal intestinal epithelium. Active accumulation of the labelled Mab in tumours was demonstrated by scintimetry. There is a demand for new diagnostic techniques for early diagnosis of colo-rectal cancer. Immunoscintigraphy must however compete with other diagnostic possibilities. The development of immunoscintigraphic technique is proceeding very rapidly, and there is probably a future for the use of immunological methods in diagnosis and therapy of cancer.

The reliability of staging and grading of bladder tumours. Impact of misinformation on the pathologist's diagnosis.

The influence of misinformation on the reliability of the histopathological classification of bladder tumours was analysed. Four consultant pathologists assessed 40 biopsy specimens of bladder tumours staging invasion and grading the specimens according to the Bergkvist classification. A random sample of 20 specimens was accompanied by systematically distorted information ("bias"-unknown to the pathologists) about previous histological grading of the patient (bias group); the other 20 specimens were used as control group (non bias group). After 6 months a second round with the same specimens was arranged to assess the influence of bias on the intraobserver variation. Using kappa (kappa) statistics the chance corrected interobserver agreement rate was poor both in staging of invasion and grading according to the Bergkvist classification (kappa < 0.50). The kappa values in the intraobserver study ranged from poor to excellent with a tendency towards lower kappa when the observer had been biased. The kappa values in the assessment of malignancy were acceptable to excellent. False information did not affect the pathologists' diagnosis significantly.

Gastrointestinal accumulation of indium-111 labelled granulocytes in reactive arthritis.

Six patients with reactive arthritis (ReA) were examined for gastrointestinal accumulation of Indium-111 labelled granulocytes. Abnormal scintigrams were found in three of six patients all of which showed early (less than 4 h) accumulation of indium-111 labelled granulocytes which may represent small intestinal inflammation. Our findings may indicate that the small intestine is involved in ReA, and that indium-111 granulocyte scintigraphy is a useful method for demonstrating inflammatory changes in the small intestine in reactive arthritis (ReA).

Indium-111-granulocyte scintigraphy in brain abscess diagnosis: limitations and pitfalls.

The scintigrams and records of 28 patients referred for indium-111-granulocyte scintigraphy (111In-GS) because of a suspected brain abscess were studied retrospectively. The final diagnosis was brain abscess in 8 patients, brain tumor in 18 patients, and infarct and hematoma in 1 patient each. Five patients not on corticosteroid treatment showed intense focal 111In accumulation in abscesses, whereas an abscess patient receiving a high steroid dose showed no uptake. Two patients studied twice showed intense uptake in abscesses when not on steroid therapy or on a low dose, whereas no uptake was seen when they received high or medium doses. Weak or moderate 111In uptake was observed in nine tumors. Microscopically assessed degree of tumor granulocyte infiltration, vessel proliferation, and hemorrhage did not correlate with the outcome of 111In GS. Our results suggest that intense focal cerebral 111In uptake favors the abscess diagnosis. Abscesses may go undetected, however, in patients on high- or medium-dose steroid therapy.

A prevalence survey of dermatoses in the Australian neonate.

A group of 420 neonates underwent total cutaneous and oral mucosal examinations during the first week of life. Skin lesions were seen in almost every baby (99.3%). The eight most common dermatoses were desquamation (65.0%), Epstein's pearls (56.0%), sebaceous hyperplasia (48.0%), milia (36%), toxic erythema (34.8%), salmon patch (33.8%), hypertrichosis (29.0%), and Mongolian spot (25.5%). Congenital melanocytic nevi were clinically diagnosed in 9 of 420 babies (2.1%); the majority of the lesions were small, that is, less than 1.5 cm in diameter. These neonates had a dark complexion (all had brown or black hair, and most had an olive skin color) and came from families with no previous history of cutaneous melanoma. In contrast, all 19 babies with a previous family history of melanoma had a fair complexion (blond or light brown hair and alabaster skin color) but no congenital melanocytic nevi. These findings may suggest that small congenital melanocytic nevi are markers for persons with a decreased risk of melanoma, because dark-skinned persons are at a lower risk. On the other hand, small congenital melanocytic nevi may be precursors of melanoma. Only prospective studies will determine the magnitude of this risk and thereby optimize management.

Studies of multilayers and thin-foil x-ray mirrors using a soft x-ray diffractometer.

A versatile x-ray diffractometer is described in detail. Two applications to the study of x-ray optical elements are presented. The first is a Bragg reflection study of state-of-the-art multilayers deposited both on conventional Si-wafer substrates and on superpolished substrates such as fused quartz and electroless nickel. These data are compared to data previously obtained at FeKα. The second study is a reflectivity and scattering study of various thin-foil x-ray reflectors proposed for up-coming x-ray satellite missions. All the data have been obtained at MgKα = 1.2536 keV.